NMR investigation and theoretical calculations on the tautomerism of benzimidazole compounds

The tautomerism of three benzimidazole compounds: Omeprazole sulfide, 1 , (R)-Lansoprazole, 2 , and Omeprazole sulfone , 3 were investigated by NMR with the effect of variant solvents and temperature. The dielectric constant of the medium and the ability of solvents to form hydrogen bond with the tautomer had a profound effect on the tautomeric equilibration. The chemical shifts and resonance lines of compounds 1–3 differed greatly in different solvent system mainly due to intra- and intermolecular hydrogen bonds. Variable temperature-nuclear magnetic resonance (VT-NMR) experiments showed that at 203 K the two tautomers of compound 1 were separated and determined to be 6:4 and those of compound 3 be 7:3. In contrast, compound 2 presented only one tautomer at the same temperature while the tautomerism was observed again with temperature increasing. The free energy of activation of the tautomeric interchange of compounds 1 – 3 were 13.77 kcal/mol, 13.47 kcal/mol and 13.06 kcal/mol, respectively. Density function theory (DFT) calculations results showed the tautomers of compound 2 had higher energy differences among the three compounds demonstrating only one preferred conformation existed at 203 K. The preferred conformations of compounds 1 and 3 were also given.